1. Field of the Invention
This invention relates generally to the field of compositions and methods for cancer and autoimmune disease research, diagnosis, and treatment. More particularly, this invention relates to fusion proteins, and pharmaceutical compositions, methods and kits comprising the same, for the treatment of cancer and autoimmune diseases.
2. Description of the Related Art
Cytokines are small cell-signaling molecules that are secreted by glial cells and cells of the immune system. They are involved in intercellular communication and stimulate proliferation or differentiation of hematopoietic cells, as well as participate in immune and inflammatory responses of the body.
The innate immune system employs a variety of cells to help protect the body. One example includes natural killer (NK) cells, which are a type of cytotoxic lymphocyte particularly involved in the rejection of tumor cells and other infected or damaged cells. NK cells act by a mechanism of killing utilizing proteins called perforin and granzyme, which cause the targeted cell to die by apoptosis, or programmed cell death. Cytokines play a large role in NK cell activation.
Interleukins are one group of cytokines that are produced by a wide variety of cells and have a significant effect on the function of the immune system. Most interleukins are synthesized by helper CD4+ T lymphocytes and monocytes, macrophages and endothelial cells, and they function to promote the development and differentiation of T, B and hematopoietic cells.
In particular, interleukin-21 (IL-21) is a member of the IL-2 cytokine family and exhibits potent and diverse regulatory effects on NK, T and B cells. Furthermore, IL-21 has been reported to possess potent anti-tumor activity against a variety of cancers not expressing IL-21 receptor (IL-21R) through activation of the immune system, and is currently in clinical trials for renal cell carcinoma and metastatic melanoma. It has previously been observed by one or more of the inventors herein that in addition to its immuno-stimulatory effects, IL-21 exerts direct cytotoxicity on IL-21R expressing diffuse large B cell lymphoma (DLBCL) cell lines and primary tumors both in vitro as well as in xenograft mouse models. Sarosiek et al., Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas. Blood. 115(3):570-80 (2010). Furthermore, preliminary data by one or more of the inventors herein and others demonstrate that IL-21 may exert similar direct cytotoxicity on mantle cell lymphoma (MCL) cell lines and primary tumors. Gelebart et al., Interleukin-21 effectively induces apoptosis in mantle cell lymphoma through a STAT1-dependent mechanism. Leukemia. 23(10):1836-1846 (2009). However, it has been detected by one or more of the inventors herein that some of the DLBCL and MCL cell lines are partially resistant to IL-21. Therefore, the field of cancer and autoimmune disease treatment and research is in need of a way to augment this effect.